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US6306434B1 - Pharmaceutical composition comprising cyclosporin solid-state microemulsion - Google Patents

Pharmaceutical composition comprising cyclosporin solid-state microemulsion Download PDF

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Publication number
US6306434B1
US6306434B1 US09/555,619 US55561900A US6306434B1 US 6306434 B1 US6306434 B1 US 6306434B1 US 55561900 A US55561900 A US 55561900A US 6306434 B1 US6306434 B1 US 6306434B1
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Prior art keywords
cyclosporin
microemulsion
pharmaceutical composition
solid
composition according
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US09/555,619
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English (en)
Inventor
Chung Il Hong
Jung Woo Kim
Nam Hee Choi
Hee Jong Shin
Su Geun Yang
Jae Hyun Kim
Jong Lae Lim
Chong Kook Kim
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Chong Kun Dang Corp
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Chong Kun Dang Corp
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Assigned to CHONG KUN DANG PHARMACEUTICAL CORP. reassignment CHONG KUN DANG PHARMACEUTICAL CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOI, NAM HEE, HONG, CHUNG IL, KIM, CHONG KOOK, KIM, JAE HYUN, KIM, JUNG WOO, LIM, JONG LAE, SHIN, HEE JONG, YANG, SU GEUN
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention is related to a pharmaceutical composition comprising cyclosporin as an active component. More specifically, the present invention is related to a pharmaceutical composition comprising cyclosporin solid-state microemulsion prepared by dispersing of cyclosporin microemulsion in enteric carrier.
  • Cyclosporin is a high molecular peptide compound consisting of 11 amino acids which achieves its potent immunosuppressive activity by inhibiting the growth and differentiation of T cells.
  • cyclosporins such as cyclosporin A, B, C, D, G, etc. depending on the structure of constituent amino acids, but cyclosporin A is preferable used in the clinical field since its pharmacological activity and clinical indication and effectiveness are well established in the art.
  • Cyclosporin is used clinically to prevent allograft rejection after transplantation of tissue or organ such as kidney, liver, heart, bone marrow, pancreas, skin, cornea, etc. And it has been applied to treat autoimmune diseases, especially inflammation disease such as rheumarthritis.
  • Cyclosporin has a unique structure, which is a cyclic oligopeptide consisting of 11 amino acids.
  • the seven amino acids of cyclosporin are N-methylated.
  • the four remaining protonated nitrogen atoms can form intermolecular hydrogen bonds with carbonyl groups, which contribute substantially to the rigidity, of the cyclosporin skeleton. Therefore, it has a remarkably hydrophobic property, and is relatively insoluble in water (for cyclosporin A. 0.04 mg/ml at 25° C.). Due to such a low water-solubility of cyclosporin, the bioavailability of cyclosporin A is known to be 30% or less.
  • cyclosporin has almost no bone marrow toxicity unlike other immunosuppressants, it has a very narrow therapeutic range.
  • Nephrotoxicity is the major adverse effect of cyclosporin. Cyclosporin shows adverse effects such as decreasing of glomerular filtration rate, increasing of reabsorption of proximal tubules, etc., dose-dependently. It has been reported that the appearance of an irreversible deterioration of nephron and the inducement of serious nephrotoxicity is a chronic toxicity of cyclosporin multiple dosing.
  • U.S. Pat. No. 4.146,499 disclosed the method using w/o microemulsion using ethanol as a hydrophilic cosurfactant.
  • U.S. Pat. No. 5.342.625 disclosed the method using non-ethanol component as a hydrophilic cosurfactant to improve the disadvantage of using ethanol.
  • the said cyclosporin microemulsion compositions still have a problem of adverse effects induced by the peak level of blood concentration of cyclosporin. Therefore, a standard dose is administered to all patients initially, and then the blood concentration of cyclosporin must be monitored continuously on each patient. Inconveniently, dose of cyclosporin must be controlled referring to monitoring result, so that allograft rejection and nephrotoxicity would be minimized.
  • the objective of present invention is the produce of a controlled release preparation that can release cyclosporin for a long time in GI tract after oral administration, while solving the problems of cyclosporin preparations of prior arts.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising cyclosporin solid-state microemulsion.
  • Cyclosporin solid-state microemulsion is a solidified product comprising cyclosporin microemulsion and carrier component. More specifically, it can be prepared by dispersing of cyclosporin microemulsion in enteric carrier.
  • the first essential component of the pharmaceutical composition comprising cyclosporin solid-state microemulsion according to the present invention is cyclosporin microemulsion.
  • a microemulsion comprises two or more immiscible liquid materials together with surfactant like emulsion, but is a thermodynamically stable and optically transparent composition unlike emulsion.
  • the microemulsion has very low surface tension and small particle size of less than 100 nm, which together result in high absorption and permeation properties of drug delivered by microemulsion.
  • any one(s) of conventional cyclosporin microemulsions can be used, but preferable ones are those that do not contain such volatile materials as ethanol, etc. It is because solidifying step is needed in the preparation of cyclosporin solid-state microemulsion.
  • cyclosporin microemulsion and “cyclosporin solid-state microemulsion” used in the present invention are brief expressions for “microemulsion preconcentrate containing cvclosporin” and “solidified product of microemulsion preconcentrate containing cyclosporin”. respectively.
  • the terms mean that they can form microemulsion spontaneously after being dissolved in such external phases as water, etc.
  • the second essential component of the pharmaceutical composition according to the present invention is enteric carrier, which is to be used in the preparation of cyclosporin solid-state microemulsion.
  • the action of carrier in the pharmaceutical composition according to the present invention is that of serving within the cyclosporin solid-state microemulsion prepared with the said carrier to prevent of the release of cyclosporin in acidic condition, while allowing a rapid release in neural or alkali condition. That is, cyclosporin solid-state microemulsion must not release cyclosporin in the stomach, rather releasing it rapidly in the upper part of the small intestine. Furthermore, the particle size (inner phase diameter) of microemulsion formed in the small intestine must be sufficiently small and, therefore, capable of being maintained at 100 nm or below.
  • the enteric carriers that can be used in the preparation of cyclosporin solid-state microemulsion are Eudragit® aqueus methacrylic polymers, (Röhm America Inc., Piscataway, N.J., USA) hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium alginate, etc.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • CAP cellulose acetate phthalate
  • sodium alginate etc.
  • Examples of Eudragit® are Eudragit® L100, Eudragit® S100, Eudragit® RS100, etc.
  • Eudragit® L100 aqueous methacrylic acid copolymers
  • HPMCP are HPMCP H-50, HPMCP H-55, etc.
  • HPMCP H-55 which is very soluble in such organic solvent as acetone, can be used preferably.
  • CAP is also useful as an enteric carrier.
  • sodium alginate such additional component as disintegrant is needed additionally because cyclosporin solid-state microemulsion prepared is disintegrated slowly.
  • one member or mixture of the said carrier materials can be used as a carrier in cyclosporin solid-state microemulsion.
  • the carrier component may further contain any pharmaceutically acceptable additives as needed.
  • the said additives include antioxidant, disintegrant, dissolution control agent, flavor, plasticizer, preservatives, coloring agents, etc.
  • cyclosporin solid-state microemulsion can be prepared preferably with cyclosporin microemulsion and carrier in the range of 1:0.1 ⁇ 3, or more preferably 1:0.2 ⁇ 2 by weight.
  • the cyclosporin solid-state microemulsion which is comprised in the pharmaceutical composition of the present invention, can be prepared by any one of methods that can produce the solidified product of the state that cyclosporin microemulsion is dispersed in carrier.
  • a specific example is when cyclosporin microemulsion is added to the solution of carrier, and mixed to be homogeneous. The solvent is then removed by such a method as evaporation under reduced pressure, spray drying etc., resulting in solidification.
  • the pharmaceutical composition of the present invention may comprise cyclosporin microemulsion together as well as cyclosporin solid-state microemulsion.
  • the pharmaceutical composition containing cyclosporin microemulsion and cyclosporin solid-state microemulsion in the proper mixing ratio can be selected, prepared in the proper dosage form (for example, the pharmaceutical composition is filled in soft capsule or hard capsule), and then used.
  • the mixing ratio of cyclosporin microemulsion and cyclosporin solid-state microemulsion is preferably in the range of 1:0.1 ⁇ 5, or more preferably 1:0.5 ⁇ 2 by weight.
  • cyclosporin microemulsion and cyclosporin solid-state microemulsion comprised in the pharmaceutical composition of the present invention, can be prepared also in the pharmaceutical preparations independently from one another, and then administered. For example, they can be filled in soft capsule and hard capsule, respectively, and then administered together.
  • the pharmaceutical composition according to the present invention is characterized in that it does not dissolve in such external phases as water and artificial gastric fluid but dissolves in artificial intestinal fluid, thereby getting the microemulsion form. And by varying the mixing ratio of the components, the inner phase diameter of the microemulsion formed can be controlled easily to be 100 nm or below.
  • the pharmaceutical composition of the present invention which is prepared according to the said descriptions, can maintain the blood concentration of cyclosporin within therapeutic range for about 1 day through only one dosing per day. Furthermore, it can avoid such adverse effects of cyclosporin as nephrotoxicity, etc. that originate from the high blood cyclosporin concentration.
  • FIG. 1 shows release of cyclosporin solid-state microemulsions prepared using various different ratios Eudragit® L100 to cyclosporin microemulsion. Key: ⁇ , Experimental example 1-A; ⁇ , Experimental example 1-B; and ⁇ , Experimental example 1-C.
  • FIG. 2 shows the mean blood cyclosporin concentrations following the single oral administration of cyclosporin microemulsion ( ⁇ ) (equivalent to 100 mg of cyclosporin A) to dogs and following the single oral combination administration ( ⁇ ) of cyclosporin microemulsion (equivalent to 100 mg of cyclosporin A) and cyclosporin solid-state microemulsion cyclosporin (equivalent to 100 mg of cyclosporin A) to dogs.
  • Cyclosporin solid-state microemulsion film produced was powdered, and formulated into pharmaceutical preparations, that is, capsule, powder, granule and tablet according to conventional methods.
  • the pharmaceutical preparations comprising cyclosporin solid-state microemulsion were prepared in the same manner as Example 1 except using HPMCP instead of Eudragit® L100.
  • the pharmaceutical preparations comprising cyclosporin solid-state microemulsion were prepared in the same manner as Example 1 except using CAP instead of Eudragit® L100.
  • the pharmaceutical preparations comprising cyclosporin solid-state microemulsion were prepared in the same manner as Example 4 except additionally using polyethylene oxide of 5 g as a dissolution control agent.
  • cyclosporin microemulsion prepared with the composition of Table 1 50 g was mixed with 100 g of the powder of cyclosporin solid-state microemulsion prepared in Example 1. And the resulting composition was poured to a machine for preparing soft capsules and then encapsulated according to conventional methods for producing soft capsules. Each capsules contained 100 mg of cyclosporin A.
  • Example 2 With 100 g of the powder of cyclosporin solid-state microemulsion prepared in Example 1, 50 g of cyclosporin microemulsion prepared with proper composition was mixed. And the resulting composition was filled in hard gelatin capsules. The conjugated portion of the hard capsules was sealed with gelatin banding to produce hard capsules containing 100 mg of cyclosporin A per capsule.
  • the pharmaceutical preparations comprising cyclosporin solid-state microemulsion were prepared in the same manner as Example 1 ⁇ 7 except using cyclosporin microemulsion of Table 2 instead of one of Table 1.
  • the pharmaceutical preparations comprising cyclosporin solid-state microemulsion were prepared in the same manner as Example 1 ⁇ 7 except using cyclosporin microemulsion of Table 3 instead of one of Table 1.
  • the cyclosporin solid-state microemulsion in the pharmaceutical composition of the present invention was designed that it does not release cyclosporin in acidic condition, but can release rapidly in neutral or alkali condition. Therefore, the release test and the absorption test in dogs were performed to prove the characteristics designed.
  • Test sample preparation 1-A was prepared as follows:
  • Test samples 1-B and 1-C were prepared in the same manner with test sample preparation 1-A except amount of Eudragit® L100 used, demonstrated in Table 4.
  • the release test was performed according to USP XXIII dissolution apparatus II procedure.
  • the paddle was set at the level of 2.5-cm distance from the bottom of the vessel.
  • Samples equivalent to 100 mg of cyclosporin A encapsulated in hard gelatin capsule was loaded in 500 ml of simulated gastric fluid (pH 1.2) (1st fluid) at 37.0 ⁇ 0.5° C. with stirring speed of 100 rpm. Each sample (4 ml) was withdrawn at 0, 30, 60, 90 and 120 min with compensation of equal volume of dissolution medium.
  • cyclosporin A concentrations of the samples were determined by HPLC (high-performance liquid chromatography) at the following condition:
  • the result of the release test was shown in FIG. 1 .
  • the cyclosporin solid-state microemulsion in the pharmaceutical composition of the present invention was stable in simulated gastric fluid and then released cyclosporin in simulated intestinal fluid rapidly and completely.
  • Test sample preparation 1-A cyclosporin solid-state microemulsioni
  • soft capsule of Table 1 cyclosporin microemulsion
  • Venous blood samples of 3 ml was withdrawn in the cephalic vein before drug administration for baseline cyclosporin A levels, and at schedule time intervals, that is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8 and 12 h, after dosing. Blood samples were frozen under ⁇ 18° C. until assay,. Blood concentrations of cyclosporin A were analyzed by RIA (radioimmunoassay) method.
  • FIG. 1 The dog-whole blood cyclosporin A concentration vs. time curves of each preparation are presented in FIG. 1 . It shows that administration of the pharmaceutical composition comprising cyclosporin microemulsion and cyclosporin solid-state microemulsion according to the present invention could maintain trough level above the lower limit of therapeutic range for about 24 h without additional increase of peak blood level.
  • the pharmaceutical composition of the present invention which comprises a solidified product of cyclosporin microemulsion of prior arts, can maintain the blood concentration of cyclosporin A within therapeutic range for about 1 day through only one dosing per day. Therefore, it is possible to avoid the adverse effects, such as nephrotoxicity, etc., induced by the additional increasing of the peak level of blood cyclosporin concentration in the conventional cyclosporin preparation, and furthermore, a convenience for administration can be obtained.

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US09/555,619 1997-02-12 1998-12-01 Pharmaceutical composition comprising cyclosporin solid-state microemulsion Expired - Fee Related US6306434B1 (en)

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PCT/KR1998/000387 WO1999027946A1 (fr) 1997-12-02 1998-12-01 Preparation pharmaceutique comportant une microemulsion de cyclosporine a l'etat solide

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